Diabetes is characterized by abnormally high levels of the sugar glucose in the bloodstream. Complications include blindness, kidney failure, heart disease, stroke, neuropathy, and amputations. Type-1 diabetes typically affects children and young adults. It occurs when the islet cells of the pancreas are destroyed and stop producing insulin. Insulin deficiency causes a disease called diabetes mellitus and, hence, administration of exogenous insulin is used to control this disease. It has been recorded by “International Diabetes Federation” in November 2014 that 387 million people have diabetes in the world and it caused 4.9 million deaths in 2014. The global health expenditure in diabetes estimated to be $612 billion. India has more diabetic patients than any other country with 32.7 millions of cases.
One of the biggest obstacles in type-1 diabetes is to deliver insulin 3-4 times in a day by injection and till date injections are the only efficient way to deliver insulin with maximum bioavailability in market. Insulin therapy has been around for 80 years, yet alternative methods of insulin delivery have been slow to emerge. The reason for this is that acids and enzymes present in stomach and intestines easily break down the protein insulin or if the technology gets succeeded then it results in very low bioavailability of the protein. Insulin promotes the entry of glucose, fatty acids and amino acids into cells and enhances glycogen, protein and lipid synthesis. Insulin is made up of two polypeptide chains namely, chain-A (21 amino acids) and chain-B (30 amino acids), which are held together by two disulfide bonds. Insulin exists as a monomer, dimer or hexamer. Each hexamer binds to Zn+2 ions which co-ordinates crystal formation within β granules. Molecular weight of insulin is 5500 dalton.
The various preparations of insulin available in the market include bovine insulin (from cattle), porcine insulin (from pig, a mixture of both, or recombinant human insulin. Since insulin has a very short life in the plasma, insulin products that last longer are also available. In these products, insulin is complexed with zinc, globin, protamine or a combination of any of these. These insulin preparations are required to be given through an injection which is very painful to take daily and also do not result in adequate reduction of glucose levels after meal. Hence, they are often given to the subject along with other anti-diabetes drugs.
Alternate routes of delivery for insulin like oral-buccal route, pulmonary route (lung alveoli), nasal delivery, transdermal, rectal and ocular have been a topic of intense R&D to improve. Among all, the oral route offers maximum advantage, from both physicians as well as patient perspectives.
Macromolecules like insulin exhibit structural and functional variations and are integral to the regulation and maintenance of all biological processes. The increased biochemical and structural complexity of insulin compared to conventional drug-based pharmaceuticals makes formulation design for oral delivery of therapeutic insulin is a very challenging and difficult task. The key to success of macromolecules like insulin as pharmaceuticals is to have in place an efficient drug delivery system that allows the drugs to gain access to their target sites at right time for proper duration.
The various oral preparations for delivery of protein macromolecules disclosed in the prior art are as follows:
1) CN102133190A—This patent application discloses transferrin protein nanoparticles for delivering drugs such as insulin. The formulation is going under high pressure homogenization to obtain insulin linked transferrin nanoparticles (approx. 250 nm). A drawback of this patent application is that the extraction of transferrin is difficult as well as high amount of transferrin (100 mg) is needed for 10-15 mg of insulin. The insulin has to undergo high pressure homogenization to link with transferrin. The formulation is showing only 20% reduction in blood glucose level. For scale-up, this formulation will be difficult to work out as well as it will be costly, since there will be more degradation of insulin protein due to homogenization process.
2) U.S. Pat. No. 7,871,988—This patent uses using chitosan and polyglutamic acid for the insulin system. Chitosan is having cationic charge and it helps in paracellular permeability of the formulation. The formulation is tested in diabetic rats and it is able to reduce 30% glucose level in 3 hours while the freeze dried formulation is not able to reduce glucose. Synthesizing chitosan is itself complex and its molecular weight varies due to which large scale production will be difficult and the particle size will not be controlled too.
3) U.S. Pat. No. 8,859,004—This patent discloses a formulation which is pH based and releases insulin from formulation at neutral pH. It consists of two polymers like PLGA and HP50/HP55 and the formulation is made by solvent evaporation step and freeze drying. The formulation is not suitable for large scale manufacturing due to the presence of residual organic solvent and it will be costly as well.
4) US20100166855—This patent application discloses a two phase system made up of dextran microparticles which are formed by solvent evaporation method. This is a costly process as well as during scale-up it may face the problem of residual organic solvent in final formulation. The formulation reduces 30% glucoses in 1 hour.
5) US20130034602—This patent application discloses a complex formulation due to double emulsions (PLGA and Eudragit RS) as well as insulin is exposed to organic solvent (polyvinyl alcohol) while encapsulation. The formulation disclosed in the patent application will be difficult to scale-up as well as not affordable and it will face problem of residual organic solvent. The formulation results in 30% reduction of glucose levels in around 7 hours.
The present invention provides an orally administrable pharmaceutical preparation containing a protein such as insulin by using metal oxide nanoparticles and an amino acid which provides a charge based system to allow easy engulfment of the protein preparation though the epithelial cells or the Peyer's patches in the gut line.